Clinical investigators are disappearing from the ranks of federally funded research portfolios to the extent that they have become an "endangered species". To counter this loss, the Training Program in Human Investigation at Thomas Jefferson University prepares investigators for enduring careers pursuing funded hypothesis-driven patient-oriented research and to be role models and mentors to subsequent investigators pursuing similar careers. This Clinical Research Curriculum is composed of a multi-disciplinary faculty with expertise in patient-oriented research, a core of relevant courses and patient-based research experiences, and mentored training in clinical investigation. Successful completion of the program requires >40 course credits and a formal research thesis and defense. Applications are solicited from a large pool (>650) of trainees drawn from different colleges within the university, as well as from clinical training programs at other health care centers in Philadelphia. Eligible applicants include house officers and subspecialty fellows, dentists, pharmacy fellows with a Pharm.D., Ph.D. fellows, and those with a doctoral degree in nursing interested in patient-oriented research. Applicants submit a written application, three letters of recommendation, and transcripts and are selected by an Advisory Committee following personal interviews. Once accepted, trainees pursue a unique program of didactic and applied research components. Formal coursework provides training in essential topics for patient-oriented research including biostatistics, epidemiology, clinical trial design, database management, outcomes research, bioethics and the responsible conduct of research, clinical pharmacology, federal policy and regulations regarding human subjects, scientific writing and grant writing. Coursework is supplemented with components that provide practical experience central to the conduct of patient-oriented research. These include (1) a clerkship in the Jefferson Clinical Research Unit in which trainees participate in a mentored clinical research experience by generating, implementing, completing, and reporting on a randomized clinical trial; and (2) identification of an interest-specific thesis question and advisor, development of a thesis proposal, and conduct of thesis research. Additional novel aspects of this training program include rotations on the Institutional Review Board (IRB) and/or Cancer Clinical Research Review Committee (CCRRC) and a clerkship in the critical review of scientific literature with the editorial staff of the Annals of Internal Medicine. Other important programmatic components include ethics seminars and conferences, journal club in clinical investigation, an in-house research seminar series, and seminars in clinical investigation with invited speakers from outside the institution. Upon completion of the program, trainees have (1) a thorough understanding of hypothesis formulation and testing in patient-based studies, (2) a theoretical foundation and working knowledge of research designs, (3) insight into the integration of laboratory-based analyses and surrogate endpoints in patient-oriented research, (4) a demonstrated record of achievement conducting randomized clinical trials and other types of studies documented through publication, (5) the ability to critically evaluate the scientific literature, and (6) the ability to employ various computer-based statistical and database packages in research-related. Upon completion of the program, trainees are qualified to perform independent clinical research with certification through a Master's of Science in Human Investigation.